I try to stop myself from opening these posts with a line like, “One of the weirdest viruses … “, or “The most bizarre viral disease … ” or whatever, because viruses are all so weird and interesting that all my posts would start that way. But anyway: One of the most interesting viral diseases is FIP (Feline Infectious Peritonitis). Except that a recent paper argues — much to my relief — that maybe FIP isn’t quite as unconventional as all that. But it’s still really interesting.

When I was in veterinary practice, FIP was one of the regular horrors we saw. First, it’s often very hard to diagnose — in its early stages it’s a “Great Pretender” disease that mimics several other diseases and often causes fairly non-specific and vague symptoms. I’m pretty sure just about every feline practitioner has missed at least one case of early FIP. Second, it’s essentially always fatal. There’s no treatment, the diseases is progressive, and I’ve never heard of a cat recovering. And without getting caught up in the more disgusting details1 it’s often a really slow and unpleasant way to die. I just hated to see it. Unfortunately, it’s a reasonably common disease.

FIP is a viral disease, or at any rate the underlying cause is a coronavirus. 2 The symptoms are actually caused by a hyperactive, but ineffective, immune response to the virus. 3 The really weird wrinkle to FIP is that the disease-causing virus is believed to be a spontaneous mutant of a very common, but benign, coronavirus that is present in the gut of most cats.

Here’s how the standard model for FIP works. This is what I teach my class in Veterinary Microbiology & Immunology each fall. 4 Cats are infected with Feline Enteric Coronavirus (FECV). It’s not a problem for the cat; maybe it causes mild diarrhea, more likely there are no symptoms. In most cats, that’s the end of the story. But in rare cases, the coronavirus mutates — the details aren’t clear, and the precise mutation isn’t known — and turns into the FIP variant of the virus, FIPV. This virus doesn’t just live in the gut, it spreads throughout the body. The cat immune system tries to control the virus, and fails. The presence of continued viral antigen continues to drive the immune response, and there’s a hyperactive response, that doesn’t clear the virus. This continuous hyperactive response is what we see as FIP disease. (There are almost certainly host factors involved, too. Probably most cats have no problem with FIPV, and only a certain genotype of cat goes into the hyperimmune state that leads to disease. But we have no idea what those factors are.)

Coronavirus

So the basic idea is that a mutation changes a harmless virus into a horrible one. There are some critical implications of this model:

The FIPV genomic sequence in a cat should be more similar to the benign FECV in that area, than to FIPV in other areas

FIP, the disease, is not infectious. Cats already have the benign virus, and the disease-causing variant doesn’t spread from one cat to the next. 5

OK, so this is a pretty unusual situation. The only similar example that comes to mind is, maybe, measles and subacute sclerosing panencephalitis. 6 Another, much more conventional, explanation would be that there are actually two distinct strains of feline coronavirus, and one of them causes FIP while the other causes benign enteric infection. There are several arguments against this more conventional model, but then on the other hand the support for the mutation model is not terribly strong — in particular, the actual, specific hypothetical mutation that changes FECV into FIPV isn’t known. Two recent papers offer some modest support for the mutation model, while two other papers argue against it.

The two supporting papers7,8 both looked at the genomic sequences of FIPV vs. FECV, and found that (as predicted by the mutation model) the FIPV overall looked like local FECV, but had unique mutations in specific genes:

Coronavirus from feces and extraintestinal FIP lesions from the same cat were always >99% related in accessory and structural gene sequences. SNPs and deletions causing a truncation of the 3c gene product were found in almost all isolates from the diseased tissues of the eight cats suffering from FIP, whereas most, but not all fecal isolates from these same cats had intact 3c genes. Other accessory and structural genes appeared normal in both fecal and lesional viruses. Deliterious [sic] mutations in the 3c gene were unique to each cat …7

(It’s worth noting that these studies didn’t do whole-genome sequencing, but rather looked at less than a third of the genome. Feline coronavirus is a medium-sized virus, at around 29 kb,9 very roughly twice as large as influenza viruses, and the resources aren’t there for the sort of large-scale genomic sequencing we see for influenza.)

One weak strike against the mutation model comes from a recent paper10 from Matti Kiuppel and Roger Maes, here at MSU. (Roger mentioned this to me last week at his student’s thesis defense,11 which is what reminded me to write about this today.) They describe a symptom very much like FIP, in ferrets, also caused by a coronavirus; but in this case, the causative virus seems to be quite clearly a different strain than the endogenous ferret enteric coronavirus, although they still interpret this as a recent mutation:

The virus present in the samples tested also was not identical to the recently described ferret enteric coronavirus, FECV-MSU1, but appears to be most closely related to it by phylogenetic analysis … Further genomic sequencing will be required to more definitively characterize this systemic ferret coronavirus. The relatively recent recognition of this disease in pet ferrets suggests the occurence of a recent mutation or shift in the FECV that results in this disease, similar to the mutations that occur in FCoV preceding the development of FIP.10

Feline coronavirus phylogeny (see Figure 4 of the original paper for detail)

So that’s circumstantial evidence that different strains could be involved. The most intriguing paper comes from Stephen O’Brien’s lab. 12 They sequenced chunks of FIPV and FECV (again, not the whole genome) and their conclusion was opposite to the previous groups: They feel that FIPV is a distinct strain of coronavirus, different from the enteric strain. Strains associated with FIP fell into one phylogenetic cluster, while those associated with enteric disease fell into a different cluster:

First, gene sequences from healthy cats infected with FECV displayed a monophyletic cluster pattern that was generally distinctive from cats diagnosed with FIP in the membrane, NSP 7b, and spike-NSP3 gene segments … Similar reciprocal monophyly of 140 NSP7b sequences was obtained for FIP cases versus FECV-asymptomatic cats (Figure 4). A consistent disease driven phylogeographic sorting was also observed for the 1,017-bp sequence spanning the spike-NSP3 genes, albeit with less statistical resolution, likely because of evolutionary constraints on gene divergence in this region (Figure 4). Together the remarkable reciprocal monophyly in these 3 genes supports the predictions of the circulating virulent-avirulent strain hypothesis illustrated in Figure 1.12

They also offer one specific, very telling, example of a cat that developed FIP during their screening. They had isolated one coronavirus before it developed disease, but the virus that was associated with disease was quite different:

However, virus isolated 7 months later in December 2004 after FIP developed in Fca-4590 fell within the FIP-case clades (also with high bootstrap), and was indistinguishable from FCoV isolated from other cats with FIP. This finding suggested that the pathogenic FIP-case type of FCoV infected this cat subsequent to its infection with an avirulent FECV and apparently replaced it. 12

I don’t have a dog in this fight, but O’Brien’s data look very compelling, and they support a really simple and conventional model, while the status quo model (though far from impossible) seems to call up a couple implausible events.

This is reminiscent of Dengue virus, in which the most severe form of the disease occurs when there’s an ineffective immune response that amplifies the infection.[↩]

A good outline is in the recent paper:Chang, H., de Groot, R., Egberink, H., & Rottier, P. (2009). Feline infectious peritonitis; insights into feline coronavirus pathobiogenesis and epidemiology based on genetic analysis of the viral 3c gene Journal of General Virology DOI: 10.1099/vir.0.016485-0[↩]

This isn’t strictly a prediction of the model as I’ve presented it. You could imagine that the virulent mutant would still be infectious. But in practice, FIP doesn’t seem to spread much if at all, and the model does account for that. [↩]

There may be other coronaviruses that do something similar, but I don’t think they’re any better confirmed than the feline situation[↩]